Abstract
1,25-Dihydroxyvitamin D3 (1,25D) induces differentiation of myeloid leukemia cells, but resistant cells are also encountered. We studied the mechanistic basis for the resistance in a model system using enhancers of 1,25D, the antioxidant carnosic acid and a kinase inhibitor SB202190. Knock-down (KD) of JNK2p54 unexpectedly increased the intensity of differentiation induced by the 1,25D, carnosic acid and SB202190 (DCS) combination. This was associated with upregulation of activated JNK1p46, and the transcription factors regulated by the JNK pathway, c-Jun, ATF2 and JunB, as well as C/EBP beta. In contrast, KD of JNK1p46 reduced the intensity of DCS-induced differentiation, and partially abrogated activation of c-Jun/AP-1 transcription factors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Abietanes / pharmacology
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Antioxidants / pharmacology
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Drug Resistance, Neoplasm
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Enzyme Inhibitors / pharmacology
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HL-60 Cells / drug effects
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Humans
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Imidazoles / pharmacology
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Leukemia, Myeloid, Acute / blood
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / pathology
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Mitogen-Activated Protein Kinase 9 / deficiency
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Mitogen-Activated Protein Kinase 9 / genetics*
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Mitogen-Activated Protein Kinase 9 / metabolism
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Plant Extracts / pharmacology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-jun / genetics
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Pyridines / pharmacology
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RNA, Small Interfering / genetics
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Transcription Factor AP-1 / genetics
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Tretinoin / therapeutic use*
Substances
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Abietanes
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Antioxidants
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Enzyme Inhibitors
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Imidazoles
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Plant Extracts
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Proto-Oncogene Proteins c-jun
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Pyridines
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RNA, Small Interfering
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Transcription Factor AP-1
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Tretinoin
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Mitogen-Activated Protein Kinase 9
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salvin
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole